J . Org. Chem., Vol. 43, No. 22, 1978 4379
Notes a n d MS w i t h t h a t obtained by the m e t h o d described above. Because o f the observed instability5J5 o f mercaptans 5a,b, the crude products were generally used w i t h o u t any chromatographic purification.
Disulfide Analogue of Prostaglandin Hz Methyl Ester (6). To a stirred solution o f 130 m g (0.32 m m o l ) o f 5b in 10 mL of methanol a t r o o m temperature was added 38 m g (0.70 m m o l ) o f sodium m e t h - , oxide, and t h e n 0 2 was bubbled t h r o u g h t h e resulting suspension.15 A f t e r 1 h, t h e reaction m i x t u r e was d i l u t e d w i t h 50 mL o f H20 a n d neutralized w i t h 0.1 N HCI. T h e methanol was evaporated under reduced pressure, and the product was isolated w i t h methylene chloride t o a f f o r d 112 m g (87%) o f nearly pure 6, w h i c h was f u r t h e r p u r i f i e d b y f i l t r a t i o n column chromatography o n silicic acid silicar CC-7. E l u t i o n w i t h e t h y l acetate--hexane, 1:3, gave fractions homogeneous by TLC (system A IX)9baffording 51 m g of 6 as a pale yellow oik3 [ a ] ~ +8.81°;CD (C 1; CH30H); [el375 +1180; [8]3300; [ 8 ] 2 5 6 t6500; [e1242 0; [8]234 -5580; [e1230 0; IR A,, ( f i l m ) 3450, 1735, 970 cm-'; R a m a n (neat) 520 cm-'; NMR 6rvrersi(CDC13) 5.40 (m, 4 H), 4.00 (m, 1 H), 3.60 (s, 3 H ) , 0.87 (t, J = 5 Hz, 3 H); mass spectrum m/e (electron impact)
398 M+(95.341,Mi- - H20 (6.47),M+ - OCH3 (13.91),M+ - S (9.42), M+ - SH (5.54), M+ - IH20 t OCH3) (7.62), M+ - (H20 S) (13.66), M+ - (H20 t SH) (13.60), M+ - CsHll (7.02),M+ - (OCH3 + HzO + SH2) (47.68);mass spectrum (chemical ionization) 455 (M+ + C4H9),437 (M++ C4Hg - HzO), 399 ( M + l),381 (M+ + 1 - HzO) base peak, 349 (M+ + 1 - H20 - S o r C H B O H ) . A l t h o u g h t h e NMR
+
+
14) F. Challenger, E. A. Mason, E. C. Holdsworth,and R. Emmett, J. Chem. SOC., 292 (1953). 15) Cf. M. Shibasaki and S. Ikegami. Tetrahedron Lett., 4037 (1977). 16) Personal communication from Dr. Deisy Henriquez, University of Havana, Cuba. See also, (a) A. Prince, F. S. Alvarez, and J. Young, Prostaglandins, 3,531 (1973); (b) W. P. Schneider, G. L. Bundy, F. H. Lincoln, E. G. Daniels, and J. E. Pike, J. Am. Chem. SOC., 99, 1222 (1977). and references cited. 17) J. Nakano, J. Pharm. Pharmacol., 21, 782 (1969). 18) P. Crabbe, G. Garcia, and C. Rius, J. Chem. S O C ,Perkin Trans. 1, 810 (1973).
Addition of Cyclic S e c o n d a r y Amines t o Benzo[ b l t h i o p h e n e and 3-Methylbenzo[ b l t h i o p h e n e Pierre Grandclaudon a n d A l a i n Lablache-Cornbier*
Laboratoire de C h i m i e Organique Physique, Uniuersite? des Sciences et Techniques d e Lille, B.P. 36,59650 Villeneuue D'Ascq, France Receiwd M a y 4 , 1976
spectrum shows some discrepancies w i t h t h a t o f the reported compound" (identical I R ) , the clean chemical ionization mass spectrum (through mie 800) would appear t o preclude any alternative dimeric or polymeric structure:s,l:' % / e 398.1940, calcd, 398.1949.
Metal-catalyzed addition of primary and secondary amines to conjugated hydrocarbons is well documented,l and a general method of ethylating amines with ethylene using an alkali Acknowledgment. We wish to thank Dr. Hayashi for metal salt of the amine as catalyst has been described.2 More kindly exchanging information. A fellowship to A.P. from the recently, Eisenbraun and co-workers have shown that, in C.I.E,.S. (Paris) is gratefully acknowledged. addition to reduction products, naphthalene and methylnaphthalenes undergo reductive amination in the presence Registry No.-Za, 13345-50-1; 2a m e t h y l ester, 31753-19-2; 2b, of sodium and secondary amines.3 We wish to report the ad36323-03-2; 3a, 6'7452-66-8; 3b, 67452-67-9; 3c, 67452-68-0; 3d, dition of cyclic secondary amines to the C Z - C ~bond of ben67452-42-0; 3e, 6'7452-43-1; 3f, 67452-44-2; 4a, 67452-45-3; 4b, 67452-46-4;5a, 67452-47-5; 5b, 61955-20-2; 6,61955-22-4;methanezo[b]thiophene (1) and 3-methylbenzo[b]thiophene(2) in the sulfonyl chloride, 124-63-0; sodium trithiocarbonate, 534-18-9; presence of an alkali metal salt of the amine. A definite asFS 15-acetate methyl 9tu,1ltu-dithiolacetoxy-9,1l-dideoxypostaglandin signment for the position of attachment of nitrogen on Cz for ester, 67452-48-6. the adducts can be made using NMR data. 2-Alkylaminobenzo[b]thiophenes are readily obtained by aromatization of R e f e r e n c e s a n d Notes the adducts. (1) Contribution no. 30 from the Laboratoire de Chimie Organique, On stirring (18 h, 40 O C ) benzo[b]thiophene 1 or 2 in a cyclic C.E.R.M.O. (2) (a) M. Hamberg and B. Samuelsson, Proc. Natl. Acad. Sci. U.S.A., 70, 899 secondary amine in the presence of dispersed sodium, an ad(1973); (b) M. Hamberg, J. Svensson, T. Wakabayashi, and 6. Samuelsson. duct is obtained in high yield (see Table I). Similar addition ibid., 71, 345 (1974); (c) M. Hamberg, J. Svensson, and B. Samuelsson, ibid., 72, 2994 (1975):(d) D. H. Nugteren and E. Hazelhof, Biochim. Biophys. is performed using an alkali metal salt of the amine instead Acta, 326, 448 (1973); (e) G. B. Kolata, Science, 190, 770 (1975); (f) S. of dispersed sodium. In this case, the anion of the amine is Moncada. R. Gryglewski. S.Bunting, and J. R. Vane, Nature (London), 263, formed by reaction of the amine with n-butyllithium or so663 (1976); (9) see also, K. C. Nicolaou, G. P. Gasic, and W. E. Barnette, Angew. Chem., Int. Ed. Engl., 17, 293 (1978). dium hydride. (3) H. Miyake, S.Iguchi, H. Itoh. and M. Hayashi, J. Am. Chem. Soc., 99,3536 We suggest nucleophilic addition of the anion of the amine (1977), and refetences cited. as the first step of the reaction. The amine is needed for the (4) G. L. Bundy and D. C. Peterson, Tetrahedron Lett., 41 (1978). ( 5 ) For recent syntheses of other thio analogues of PGFz, see: (a) K. C. Nicoprotonation of the intermediate carbanion, as supported by laou. W. E. Barnette, G. P. Gasic, and R. L. Magolda, J. Am. Chem. SOC., the failure of addition of sodamide in toluene or the lithio salt 99, 7736 (1977);(b)K. C. Nicolaou, R. L. Magolda, and W. E. Barnette, J. Chem. SOC.,Chem. Commun., 375 (1978);(c) M. Shibasaki and S. Ikegami. of piperidine in hexane on 1 (Scheme I). Tetrahedron Lett., 559 (19781, and references cited. When similar reactions are performed on 2-methylben(6) (a) P. Crabbe. Tetrahedron. 30, 1979 (1974); (b) P. Crabbe, E. Barreiro, H. S.Choi. A. Cruz, J. P. Depres. G. Gagnaire, A. E. Greene, M. C. Meana, A. zo[b]thiophene, 2,3-dimethylbenzo[b]thiophene,benzo[ b ]Padilla, and L. Williams, Bull. SOC. Chim. Belg., 86, 109 (1977); (c) C. V. furan, or benzo[b]selenophene, no addition has been detected. Grudzinskas and M. J. Weiss, Tetrahedron Lett., 141 (1973),and references Heterocycles are recovered unreacted except benzo[b]selencited. Under more vigorous conditions, the C-11 isomer could be observed as a minor product. See ref 6c. ophene, which is reduced to ethylbenzene. (7) Zinc borohydride in dimethoxyethane affords predominantly the 96 alcohols When a low molecular weight primary amine. e.g., propin the reduction of 1ldeoxypostaglandin E2 (unpublishedresults from these laboratories), PGEz,5aand 11-epiprostaglandinEZ8derivatives. la mine,^ is substituted for a cyclic secondary amine in reac(8) E. J. Corey, K. C. Nicolaou, Y. Machida, C. L. Maimsten, and 6. Samuelsson, Proc. Natl. Acad. Sci. U.S.A., 72, 3355 (1975). (9) (a)K. seen and B. Samuelsson, J, LipidRes., 5, 117 (1964); (b) M. Hamberg and B. Samuelsson, J. Biol. Chem., 241, 257 (1966); (c) N. H. Andersen, ibid.. 10, 316 (1969); (d) E. J. Corey, K. C. Nicolaou, and M. Shibasaki, J. Chem. SOC.,Chem. Commun., 658 (1975). (10) See, for example: J. F. Bagli and T. Bogri, Tetrahedron Lett., 5 (1967); M. Miyano, C. R. Dorn, andR. A. Mueller, J. Org. Chem., 37, 1810(1972); E. Martinez, J. M. Muchowski, and E. Veiarde, J. Org. Chern., 42, 1087 (1977). (11) E. J. Corey and R. K. Varma, J. Am. Chem. Soc., 93, 7319 (1971); R. E. Schaub and M. J Weiss, Tetrahedron Lett., 129 (1973). (12) D. J. Martin and C. C. Greco, J. Org. Chem., 33, 1275 (1968). (13) Initial results indicate that 4b acts as a biochemical mimic rather than antagonist of the prostaglandin endo-peroxides. This represents further ew' idence that mimicry is not restricted to the heterobicyclo[2.2. llheptane analogues of the prostaglandin endoperoxides. See, P. S.Portoghese, D. L. Larson. A. G. Abatjoglou, E. W. Dunham, J. M. Gerrard, and J. G. White, J. Med. Chem., 20, 320 (1977).
-Scheme I
QQ22-3263/78/1943-4319~Q1.QQIQ @ 1978 American Chemical Society
-
4380 J. Org. Chem., Vol. 43, No. 22,1978
Notes
Table I. Addition of Amines to Benzo[ blthiophenes
--
Amine
Benzo[b]thiophene recovered, %
Registry no.
Pyrrolidine Piperidine Piperidine' Morpholine t, Morpholined Diethylamine
Adduct
Registry no.
Yield,a %
3 4 4
66966-29-8 41216-62-0
5 5
66902-30-5
6'
66902-29-2
50 51 46 45 41 5
66902-24-7 66902-23-6
52 55 42 2 4
Benzo[b]thiophene (1) 10 12 21 15 29 75
123-75-1 110-89-4 110-91-8 109-89-7
3-Methylbenzo[b]thiophene(2) Pyrrolidine Piperidine b Morpholinet' Propylaminebf Cyclohexylamine
bjf
5 4 12 5 72
107-10-8 108-91-8
7 8 9 10' 11e
Reaction in the presence of dispersed sodium. Anion formed by reaction of a Yield is based on consumed benzo[b]thiophene. amine with n-butyllithium. Anion formed by reaction of amine with sodium hydride. e Characterized only through mass spectra. f At room temperature.
Scheme I1
'J
12
5 9
13
tion with dispersed sodium, 1 is reduced t o ethylbenzene (60%),2-ethylthiopheno1(20%),5 and o-ethylphenyl disulfide (lo%), and 2 gives cumene (90%). With cyclohexylamine or a n acyclic secondary amine, small amounts of reduction products are formed b u t yields of adduct are very low.6 No reaction with other nucleophilic anions, e.g., an alkali metal salt of thiophenol or alcohols, can be detected. T h e NMR d a t a for adducts 7, 8, and 9 on 3-methylbenzo[b]thiophene allow the definite assignment for the position of attachment of the amino group on Cz and suggest that these adducts are a mixture of trans (major product 95%) a n d cis isomers.' In each case, on VPC analysis of the crude amino derivatives a small amount of 2-alkylaminobenzo[b]thiophene(12, 1319 can be detected. These products are readily obtained by aromatization of t h e adducts with stoichiometric amounts of sulfurlo (Scheme 11). E x p e r i m e n t a l Section Benzo[b]thiophene was purchased and recrystallized. 3-Methylbenzo[b]thiophene was synthesized according to Werner" and distilled. All amines were distilled twice from KOH under dry nitrogen. All melting points are uncorrected. IR spectra were determined using a PE 157G instrument, NMR spectra were recorded on a 60 CHL Jeol spectrometer in CDC13 using Me4Si as an internal standard, and mass spectra were determined using a MS 1 2 spectrometer (University of Bordeaux, France) or a RIBERMAG 10.10. VPC analyses were performed on a F & M 810 GC 6 ft X 0.25 in column packed with 10%SE-30 on Chromosorb W. Reactions with Dispersed Sodium. General Procedure. To 3.5 g (0.15 g-atom) of dispersed sodium in 60 mL of amine was added a 0.03 M solution of the benzo[b]thiophene (1,4 g; 2,4.5 g) in 10 mL of amine. The mixture turned red-brown within half an hour and was stirred at 40 O C under dry nitrogen for 18 h. Unreacted sodium generally agglomerated and was removed. The reaction mixture was poured into ice water, acidified with aqueous HCl, and extracted with ether to discard unreacted benzo[b]thiophene.The aqueous layer was
made basic with KOH and extracted with ether. The adduct-carrying ether layer was dried (NazS04) and concentrated. The crude adduct was purified by chromatography on alumina and was recrystallized from heptane-toluene when a solid. 2-Pyrrolidino-2,3-dihydrobenzo[ blthiophene (3). Reaction of 1 with pyrrolidine: 3.1 g (50%);IR (cc4)3060,2950,2870,2810,1585, 1460,1445,1360,1120,1060,740cm-1; NMR (CDC13) 6 1.6 (m, 4 H), 2.4 (m, 4 H), 3.2 (q, 1 H, 53.3' = 16.5 Hz, J 2 , 3 , = 8 Hz, C3-H), 3.4 (q, 1 H, 53,3, = 16.5 Hz, J 2 , 3 = 2.5 Hz, C3-H),5.3 (dd, 1 H, CZ-H),6.9 (m, 4 H, aromatic H); mass spectrum, mle (relative intensity) 205 (M+,24), 172 (9),170 (5), 136 (30), 135 (67),134 (loo), 133 (81,121 (38),91(76), 90 (20),89 (31), 78 (20), 77 (33),70 (57),69 (33). Anal. Calcd for C1zH1bNS: C, 70.20;H, 7.36; N, 6.82; S, 15.61.Found: C, 70.37; H, 7.42; N, 6.80; S, 15.97. 2-Piperidino-2,3-dihydrobenzo[ blthiophene (4). Reaction of 1 with piperidine: 3.35 g (51%);IR (CC4) 3060.2940, 2860, 2805, 1580, 1460,1445,1230,1205,1120,1060,990,860,740cm-I; NMR (CDC13) 6 1.4 (m, 6 H), 2.35 (m, 4 H), 3.2 (q, 1 H, 53.3. = 16.5 Hz, 52,:3,= 7.5 Hz, C3-H), 3.6 (4, 1 H, 53,y = 16.5 Hz, 52,3= 3 Hz, C3-H), 5.1 (dd, 1 H, Cz-H),7 (m, 4 H, aromatic H); mass spectrum, m/e (relative intensity) 219 (M+,48), 186 (8),137 (8),136 (31),135 (48). 134 (30),96 ( 3 8 ) ,91 (23),85(15),84 (100). Anal. Calcd for C13H17NS: C, 71.20; H, 7.82; N. 6.39. Found: C, 70.93; H, 7.82; N, 6.18. 2-Morpholino-2,3-dihydrobenzo[blthiophene ( 5 ) . Reaction of 1 with morpholine: 3 g (45%);mp 75-76 "C; IR (CCl4)3060,2960,2850, 1580,1460,1445,1120,1060,1020,995,920 cm-'; NMR (CDC13)6 2.45 (m, 4 H), 3.3 (4, 1 H, J 3 , y = 16.5 Hz, 52,3, = 8 Hz, C3-H),3.6 (q, 1 H. 53,s) = 16.5 Hz, Jz,3 = 2.5 Hz, Cs-H), 3.65 (m, 4 H), 7.1 (m, 4 H, aromatic H): mass spectrum, mle (relative intensity) 221 (M+,67), 188 (4), 136 (32), 135 (loo), 134 (751,121(8),98 (32).91 ( 3 7 ) ,86 (30),77 (12).
Anal. Calcd for C1zH15NOS: C, 65.12; H, 6.83; N. 6.33: 0,7.23; S. 14.49. Found: C, 64.90; H, 6.91; N, 6.45; 0, 7.53; S, 14.31. 2-Pyrrolidino-3-methyl-2,3-dihydro benzo[ blthiophene (7). Reaction of 2 with pyrrolidine: 3.4 g (52%);IR (CCl4)3060,2950,2860, 2805, 1585, 1460, 1440, 1355, 1250, 1070, 1020, 870, 790, 740 cm-I: NMR (CDCI3) 6 1.35 (d, 3 H, J = 7 Hz, CH:3),1.7 ( m , 4 H), 2.55 (m, 4 H), 3.4 (dq, 1 H, 5 2 , 3 = 3 Hz, C3-H), 5.0 (d, 1 H, Cz-H),7.0 (m, 4 H, aromatic H); mass spectrum, mle (relative intensity) 219 (M+,49), 186 (8),149 (49), 148 (100),147 (35), 135 (21), 134 (281; 115 (ll), 96 (21), 91 (13),84 (21), 70 (75). Anal. Calcd for C13H17NS: C, 70.93: H. 7.68; N, 6.51;S, 14.87.Found: C, 71.19;H, 7.80; N, 6.38; S, 14.62. 2-Pi~eridino-3-meth~l-2.3-dihvdrobenzol blthioDhene (8). Reaction of 2 with piperidine: 3.85 g 65%);IR (C&j 3066,2930,2850, 2800, 1580, 1460, 1445, 1230, 1205, 1115, 1105, 1060, 990, 860, 740 cm-l; NMR (CDC13)8 1.3 (d, 3 H, J = 7.5 Hz, CH3), 1.4 (m,6 H), 2.35 (m, 4 H),3.4 (dq, 1 H, J2,3 = 3 Hz, C3-H), 4.6 (d, 1 H, CZ-HI,7 (m, 4 H, aromatic H); mass spectrum, mle (relative intensity) 233 (M+, 451, 150 (22), 149 (66),148 (loo), 147 (22), 135 (22), 134 (22), 110 (20),96 (20),85 (25),84 (78). Anal. Calcd for CldHlgNS: C, 72.05; H, 8.21; N, 6.00; S, 13.74.Found: C, 71.85; H, 8.06; N, 6.21; S, 13.57. 2-Morpholino-3-methyl-2,3-dihydrobenzo[ blthiophene (9).
J.Org. Chem., Vol. 43, No. 22, 1978
Notes Reaction of 2 with morpholine: 2.85 g (42%);mp 64-65 OC; IR (cc14) 3060, 2960, 2850, 1580, 1460, 1440,1250, 1130, 1115, 1010,905,860, 690 cm-'; NMR (CDC13) 6 1.3 (d, 3 H, J = 7 Hz, CH3), 2.45 (m, 4 H), 3.4 (dq, 1H, 5 2 , 3 = 2.5 Hz, C3-H),3.6 (m, 4 H), 4.65 (d, 1H, C2-H),7.1 (m, 4 H, aromatic H); mass spectrum, mle (relative intensity) 235 (M+, 36), 202 (4), 149 (loo),148 (92),147 (60), 135 (281,134 (641,114 (16), 115 (24), 105 (16), 103 (16), 100 (34), 91 (251, 77 (28). Anal. Calcd for C13Hl;NOS: C, 66.34; H, 7.28; N, 5.95; 0,6.80; S, 13.62. Found: C, 66.35; H, 7.16; N, 6.16; 0,6.99; S,13.74. Reaction of Piperidine and Benzo[ blthiophene by Means of n-Butyllithium. n-Butyllithium (0.15 M, 20% solution in hexane) was added to 60 mL of piperidine under nitrogen. The temperature of the mixture was maintained at 40 OC, and a solution of 4 g (0.03 M) of benzo[b]thiophene in 10 mL of amine was added. Reaction and isolation were performed as previously described. 2-Piperidino2,3-dihydrobenzo[b]thiophene(4)was purified by chromatography, 3 g (46%). Reaction of Morpholine and Benzo[ blthiophene by Means of Sodium Hydride. A mixture of 60 mL of morpholine and 3.6 g (0.15 M) of NaH was refluxed under nitrogen until the evolution of hydrogen ceased and was cooled to 40 "C. The addition of benzo[b]thiophene and the reaction procedure were as previously described. 2-Morpholino-2,3-dihydrobenzo[b]thiophene ( 5 ) was recrystallized from heptane-toluene, 2.7 g (41%). 2-Morpholinobenzo[ blthiophene (12). A 1.1-g (0.005 mol) amount of 5 and 0.16 g (0.005 mol) of sulfur were heated at 250 "C until the evolution of H2S ceased (5 min). The reaction mixture was taken into benzene and decolorized with Norit. Evaporation of benzene and recrystallizationfrom toluene-heptane gave a colorless solid: 0.65 g (60%);mp 179-180 "C; IR (CC14) 3060,2960,2900,2855,2815, 1530,1440,1120,1030,930,900,870,650cm-l; NMR (CCla)& 3.2 (m, 4 H), 3.9 (m, 4 H I ,6.2 (s. 1 H, C3-H),7.3 (m, 4 H, aromatic H);mass spectrum, rnle (relative intensity) 219 (M+, loo), 204 (6), 162 (23), 161 (93), 160 (381, 147 (141, 135 (81, 134 (261, 133 (9), 89 (201, 80 (12).
Anal. Calcd for C12H13NOS: C, 65.72; H, 5.97; N, 6.39; 0, 7.30; S, 14.62. Found: C, 65.71; H, 5.95; N, 6.35; 0, 7.55; S, 14.58. 2-Morpholino-3-methylbenzo[blthiophene (13). From aromatization of 100 mg of 9 with 15 mg of sulfur: 65 mg (65%);mp 79-80 "C; IR (CC14) 3060, 2960. 2900, 2855, 2820, 1575, 1435, 1190, 1120, 1045, 1015, 980, 880 cm-I; NMR (Cc14) 6 2.3 (s, 3 H, CH3), 3.0 (m, 4 H), 3.9 (m, 4 H), 7.4 (m, 4 H, aromatic H); mass spectrum, rnle (relative intensity) 234 (181,233(M+, 1001,232 (271,218 (51, 188 (51,176 i l l ) , 175 (50),174 (58), 173 (16), 161 (12), 160 (301,159 (lo),147 (30), 134 (11). Anal. Calcd for ClnHlsNOS: mol wt 233.0874. Found (high-resolution mass spectrum): mol w t 233.0876.
Facile S y n t h e s i s of 2-Substituted Imidazoles Kenneth L. Kirk Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014 Received June 13,1978 Continuing studies in the biochemistry and pharmacology of ring-fluorinated imidazoles have revealed striking differences in behavior between 2- and 4-flUOrO isomers in each series.1 For example, 2-fluorohistidine displays a wide range of biological activities2 while 4-fluorohistidine shows little or no activity in t h e same systems. As part of our efforts to elucidate the causes of these differences, we wished to extend our testing t o isomer pairs of t h e other haloimidazoles-particularly t h e halohistidines. T h e 4 (or 5)-halo derivatives can be obtained by direct electrophilic substitution,3 but no methods are available for preparation of the 2-halo isomers. While 2fluoro-4 and 2-chloroimidazoles5 have been prepared by photochemical decomposition of 2-diazoniumimidazoles, the method fails for bromine or iodine, and there exists no obvious procedure for the introduction of the latter halogem6 We have now developed a general synthesis, not only for 2-haloimidazoles, b u t for a variety of other 2-substituted imidazoles. In 1-alkyl or 1-arylimidazoles (methyl, benzyl, phenyl), H-2 is t h e most acidic hydrogen and a carbanion is readily generated at C-2 by reaction with n-butyllithium; this carbanion has been used for addition to carbonyl groups7 as well as t o other electrophilic reagents8 Unfortunately, the 1-substituent is not easily removed from the product in these cases. N Benzylimidazole can be debenzylated with sodium in liquid ammonia? b u t bromine or iodine a t C-2 undoubtedly would be removed a t t h e same time. We have found t h a t 1-tritylimidazolelO also forms a carbanion (1) with n-butyllithium,
1
Registry No.--l,95-15-8; 2,1455-18-1; cis-7,66902-28-1; trans-7, 66902-27-0;cis- 8,66902-26-9; trans- 8,66902-22-5; cis- 9,66902-21-4; trans- 9,66902-20-3: 12, 18774-55-5; 13,66902-25-8. References a n d Notes (1) (a)R. Wegler and G. Pieper, Chem. Ber., 83, 1 (1950); (b) H. Bestian, Justus Liebigs Ann. Chem., 566, 210 (1950). (2) R. D. Ciosson, ,I. P. Napoiitano, G. G. Ecke, and A. J. Koika, J. Org. Chem., 22, 646 (1957) (3) (a)L. E. Harris, D. V. Hertzier, 0. C. Dermer, and E. J. Eisenbraun, J. Org. Chem., 37,3039 (1972); (b) E. J. Eisenbraun, R. C. Bansal, D. V. Hertzier, W. P. Duncan, P. W. K . Flanagan, and C. M. Hamming, hid., 35, 1265 (1970); (c)R. C. Bansai, E. J. Eisenbraun, and P. W. Flanagan, J. Am. Chem. Soc., 88, 1837 (1966). (4) R. A. Benkeser, R. K. Agnihotri. M. L. Burrous, E. M.Kaiser, J. M.Mailan, and P. W. Ryan, J, Org. Chem., 29, 1313 (1964). (5) Birch-type reduction of 1 has been effected by the milder reducing system
sodium-ethanol-ammonia to give 2-ethylthiophenol: W. Huckel and I. Nabih, Chem. Ber., 89, 2115 (1956). (6) When the reaction is performed with n-butyliithium and a primary amine, no reduction products are formed but the yield of adduct remains disappointingly low.
(7) Cis and trans isomers of adducts 7,8, and 0 cannot be separated,even at
an analytical scale. The assumption that the major product is the trans isomer is based on literature data assuming that the chemical shift of H2 should be higher in the cis isomer than in the trans isomer and that J2.3 is higher when H2 and H3 are cis than when they are trans8 (8) (a)L. M. Jackman and S. Sternhell, "Application of NMR Spectroscopy In Organic Chemistry", 2nd ed, Pergamon Press, Oxford, 1969, p 233; (b) J. J. Christol, T. W. Russel, J. R. Mohrlg, end D. C. Plorde, J. Org. Chem., 31, 581 (1966).
(4)The yield is less then 1% based on consumed benzo[b]thiophene. (a)K. R. Brower and E. D. Amstutr, J. Org. Chem., 18, 41 1 (1954); (b) 8 . lddon and R . M. Scrowston, Adv. Heterocycl. Chem., 11, 177 (1970). (I 1) E. G. G. Werner, Red. Trav. Chlm. Pays-Bas, 88, 509 (1949).
(10)
4381
2
3
t h a t t h e carbanion reacts readily with various electrophiles t o form 1-trityl-2-X-imidazoles(Z), and that the trityl group is easily removed by mild acid hydrolysis to give 2-X-imidazoles (3). Tables I and I1 describe compounds prepared by this general method. Yields of 2 are consistently high,ll except where X is halogen. Attempts to improve yields in the halogenation steps by variation in conditions or source of halogen were unsuccessful. Unreacted tritylimidazole accounted for most of t h e material loss in these cases. T h e presence of a single imidazole proton resonance in the NMR spectrum of each 3 supports assignment of the substituent to the 2-position. For 3c, 3d, a n d 3g, structural assignments were confirmed by comparison with authentic samples. In no case was there formed a detectable quantity of the isomeric 4(5)-X-imidazole, based on N M R and chromatographic evidence. T h e preparation of 2-aminoimidazole through t h e phenyltriazene (2g), based on a procedure for t h e preparation of l-alkyl-2-aminoimidazoles,~2 has special significance in t h a t it allows a nonreductive introduction of the 2-amino function into a preformed imidazole ring. (In our hands, the catalytic reduction of 2-arylazo-4-X-imidazoles often results in simultaneous loss of the 4-X substituent.5) Consistent with the results of others,lZ our attempts t o aminate 1 with methoxyamine,13 O-mesitylenesulfonylhydroxylamine,*4 or 0-2,4dinitrophenylhydroxylaminel5were unsuccessful.
This article not subject t o U.S. Copyright. Published 1978 by t h e American Chemical Society
